Entries in schizophrenia (1)


New dopamine D3 receptor agonist shows promise for negative and cognitive symptom relief in schizophrenia

Schizophrenia is a highly heterogeneous psychiatric illness that affects approximately 1% of the 
population. Three major classes of symptoms (positive, negative, and cognitive) define this 
illness. Positive symptoms refer to “above normal” and include two main features, delusions and 
hallucinations. Negative symptoms refer to “below normal” and include many behaviors 
associated with depression. Cognitive symptoms refer to a fundamentally disorganized thought 
process. Currently, there is no molecular or imaging biomarker for schizophrenia. Diagnoses are 
made on the basis of symptoms through direct clinical interview. Notably, symptoms will 
be different for each patient and may change over time.
The cause of schizophrenia is not well understood and there is no cure. Two types of 
medications (typical and atypical antipsychotics) are currently used for symptom management. 
Typical anti-psychotics, such as chlorprozamine and haloperidol, are strong dopamine D2 
receptor antagonists. Typical antipsychotics are not the preferred method of treatment because 
they often cause strong movement-related side effects reminiscent of Parkinson's disease. 
Atypical antipsychotics, such as aripiprazole and clozapine, are weak dopamine D2 antagonists. 
Atypical antipsychotics often result in metabolic-related side effects including sedation, 
hypotension, and weight gain. Overall, current antipsychotic medications are intolerable and 
largely ineffective for negative and cognitive symptoms. These untreated symptoms can be 
devastating. Patients often suffer unemployment, homelessness, and drug addiction; 
approximately 10% of patients commit suicide1.
Undoubtedly, new medications are desperately needed to better manage schizophrenia. 
However, novel treatment mechanisms have not been discovered in over sixty years! 
Cariprazine may be a step in the right direction. Cariprazine, developed by Gedeon 
Richter, preferentially acts as a dopamine D3/D2 receptor partial agonist2. The dopamine D3 
receptor is implicated in mood regulation and cognition3. A recent phase III clinical trial showed 
that cariprazine significantly reduces positive, negative, and cognitive symptoms in patients 
suffering severe acute psychosis2. In this multinational double-blind study, patients were 
randomized (1:1:1:1) to receive placebo (n=153), cariprazine 3 mg/d (n=155), cariprazine 6 
mg/d (n=157), or aripiprazole 10 mg/d (n=152) for six weeks2. The primary outcome 
measurement was the mean change from baseline to week 6 in the Positive and Negative 
Syndrome Scale (PANSS) total score, which measures overall symptom severity4. Both doses 
of cariprazine significantly improved all PANSS subscales, including the depression cluster, 
within 3 weeks2. Further, the 6mg/d cariprazine dose showed a 50% PANSS response 
improvement from baseline, as compared to placebo2. Akathisia (an inability to sit) was the most 
frequent treatment-related side effect and encouragingly, cariprazine was not associated with 
metabolic-related side effects2. Based on this study and many others, cariprazine (VRAYLAR) is 
now FDA-approved for schizophrenia and bipolar disorder I-related mania2.
Clinicians suggest however, that cariprazine is not yet a “home-run”2. Future studies are 
required to test cariprazine head-to-head with commonly prescribed antipsychotics in stabilized 
schizophrenic patients2. This is particularly important, as negative and cognitive symptoms 
commonly decrease with antipsychotic treatment in patients suffering acute psychosis5. A true 
cariprazine victory would arise from strong negative and cognitive symptom reduction in the 
stabilized schizophrenic population.


Figure taken from: Durgam S. et al., Cariprazine in Acute Exacerbation of Schizophrenia: A Fixed-Dose, Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Trial. J Clin Psychiatry 76(12):e1574–e1582 (2015).


1) Saha S. et al., A systematic review of mortality in schizophrenia. Is the differential mortality gap 
worsening over time? Arch Gen Psychiatry 64, 1123-1131 (2007).
2) Durgam S. et al., Cariprazine in Acute Exacerbation of Schizophrenia: A Fixed-Dose, Phase 3, 
Randomized, Double-Blind, Placebo- and Active-Controlled Trial. J Clin Psychiatry 76(12):e1574–e1582 
3) Sokoloff P. et al., The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric 
disorders. CNS Neurol Disord Drug Targets 5(1):25–43 (2005).
4) Kay S.R., Fiszbein A., and Opler L.A. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Scizophrenia Bulletin 13(2) (1987).
5) Kirkpatrick B. et al., The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 
32(2):214–219 (2006).